Obesity and diabetes are frequently linked diseases, although some patients with one condition do not suffer from the other. The multiple causes of obesity are a subject of ongoing research. Insulin resistance and beta-cell dysfunction are two important factors contributing to the development of diabetes. The relationship between these two factors has been extensively studied, as has the role of obesity in diabetes. In particular, it has been widely observed that obesity is a principal cause of insulin resistance. Most patients who develop type II diabetes are obese.
As described in an article by Michael Gershon entitled, “The enteric nervous system: A second brain” (Hospital Practice, July, 1999), which is incorporated herein by reference, the enteric nervous system (ENS) is a portion of the autonomic nervous system which consists of two layers. The first layer is called the myenteric (Auerbach's) plexus, and lies between the layers of circular and longitudinal muscle lining the gut wall. The second layer is called the submucosal plexus, and lies between the layer of circular muscle and the submucosa. The myenteric plexus contains neurons responsible for motility and for mediating the enzyme output of adjacent organs. The smaller, submucosal (Meissner's) plexus contains sensory cells that communicate with the neurons of the myenteric plexus, as well as motor fibers that stimulate secretion from epithelial crypt cells into the gut lumen. Electrical coupling between smooth muscle cells enables signals to rapidly alter the membrane potential of even those cells that have no direct contact with neurons and ensures that large regions of bowel—rather than small groups of muscle cells—will respond to nerve stimulation.
PCT Patent Publication WO 2005/007232 to Ben-Haim et al., which is incorporated herein by reference, describes a method and apparatus for treating a subject. An electrical signal is applied to at least one stomach site of the subject. The electrical signal is configured to reduce a rise in a blood glucose level of the subject, in order to treat the subject. A colonic stimulation system is also described, comprising a control unit and one or more electrodes, which are adapted to be applied to respective sites in a vicinity of a colon or a distal small intestine of a patient. The control unit drives the electrodes to apply electrical signals to the sites, and configures the signals to stimulate L-cells or other target tissue, which, responsive to such stimulation, increase secretion of glucagon-like-peptide-1 (GLP-1). Such secretion of GLP-1 is described as generally improving glycemic control of the patient, and therefore serving to treat patients suffering from insulin-resistance-related conditions, such as obesity, NIDDM, heart disease, and hypertension, or healthy patients considered at risk for such conditions. For some applications, the colonic stimulation system further comprises an eating detection unit, and the control unit is configured to drive the electrodes to apply the signals responsive to a detection of eating.
U.S. Pat. No. 6,091,992 to Bourgeois et al., which is incorporated herein by reference, describes a method and apparatus for providing electrical stimulation to the gastrointestinal tract. The apparatus features an implantable pulse generator which may be coupled to the gastric system through one or more medical electrical leads. In the preferred embodiment the leads couple to the circular layer of the stomach. In one embodiment, the implantable system includes a hermetically sealed implantable pulse generator, the pulse generator emitting a first type of electrical stimulation at a first rate and a second type of electrical stimulation at a second rate.
The following patent publication and articles, all of which are incorporated herein by reference, may be of interest:    U.S. Pat. No. 6,191,102 to DiMarchi et al.    Todd J F et al., “Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus,” Eur J Clin Invest 27(6):533-6 (1997)    Gutniak M K et al., “Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM,” Diabetes Care 17(9):1039-44 (1994)    Robertson M D et al., “The influence of the colon on postprandial glucagon-like peptide 1 (7-36) amide concentration in man,” J Endocrinol 161(1):25-31 (1999)    Schirra J et al., “Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1 (7-36) amide in non-insulin dependent diabetes mellitus,” J Endocrinol 156(1):177-86 (1998)    Todd J F et al., “Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early type 2 diabetes,” Clin Sci (Lond) 95(3):325-9 (1998)    Vilsboll T et al., “Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients,” Diabetes 50(3):609-13 (2001)    Zhao X T et al., “Electric stimulation of small intestine delays gastric emptying in the dog model” [abstract], Neurogastroenterol Motil 14: 457 (2002)    Qian L W et al., “Normalization of atropine-induced postprandial dysrhythmias with gastric pacing,” Am J Physiol 276:G387-92 (1999)    Chen J D Z et al., “Gastric electrical stimulation with short pulses reduces vomiting but not dysrhythmias in dogs,” Gastroenterology 124: 401-9 (2003).
U.S. Pat. No. 6,322,560 to Garbagnati et al., which is incorporated herein by reference, describes a catheter for the treatment of tumors by hyperthermia induced by radiofrequency or other energy. The catheter comprises a tubular body having a cooled metal plate capable of acting as an active electrode. One application described is the treatment of pancreatic tumors by introducing the catheter through the main pancreatic duct by endoscopy or during surgery.
U.S. Pat. No. 6,575,969 to Rittman, III et al., which is incorporated herein by reference, describes a fluid-cooled (perfusion-cooled) high-frequency electrode. In one embodiment, the electrode comprises a “stint,” a balloon, or a condom-like structure that can be inserted into the pancreatic duct, and by appropriate cooling in conjunction with RF heating, it can “throw” the heat into a pancreatic tumor while sparing the structure of the duct to preserve normal processing of biological fluids.
U.S. Pat. No. 5,188,104 to Wernicke et al., which is incorporated herein by reference, describes a method for treating patients with compulsive eating disorders, including detecting a preselected event indicative of an imminent need for treatment of the specific eating disorder of interest, and responding to the detected occurrence of the preselected event by applying a predetermined stimulating signal to the patient's vagus nerve appropriate to alleviate the effect of the eating disorder of interest. For example, the preselected event may be a specified level of food consumption by the patient within a set interval of time, or the commencement of a customary mealtime according to the patient's circadian cycle, or the passage of each of a sequence of preset intervals of time, or the patient's own recognition of the need for treatment by voluntarily initiating the application of the stimulating signal to the vagus nerve. In cases in which the disorder is compulsive eating to excess, the stimulating signal is described as being predetermined to produce a sensation of satiety in the patient.
US Patent Application Publication 2005/0021101 to Chen et al., which is incorporated herein by reference, describes a method for regulating gastrointestinal action in a subject using a stimulatory electrode and a sensor to provide retrograde feedback control of electrical stimulation to the GI tract. Also described is a method for reducing weight in a subject, using a stimulatory electrode and a sensor to provide retrograde feedback control of electrical stimulation to the stomach. Further described is a method for providing electrical field stimulation to a gastrointestinal organ, as well as a method of providing an electrical potential gradient in a gastrointestinal organ. Further described is a method for stimulating the vagus nerve of a subject, by positioning a stimulatory electrode in a gastrointestinal organ of the subject. Additionally described is a method of placing a device in the gastrointestinal tract or wall of a subject from the exterior of the subject, using a needle to insert the device.
PCT Publication WO 00/53257 to Darwish et al., which is incorporated herein by reference, describes a pancreatic controller comprising a glucose sensor; at least one electrode, for electrifying an insulin producing cell or group of cells; a power source for electrifying the electrode with a pulse that does not initiate an action potential in the cell and has an effect of increasing insulin secretion; and a controller which receives the sensed level and controls the power source to electrify the electrode to have a desired effect on the level.
US Patent Application Publication 2003/0055464 to Darvish et al., which is incorporated herein by reference, describes a pancreatic controller comprising at least one electrode adapted for electrifying at least a portion of a pancreas; and a controller programmed to electrify the electrode so as to positively control at least the effect of at least two members of a group consisting of blood glucose level, blood insulin level and blood level of another pancreatic hormone.
PCT Publications WO 04/021858 and WO 05/023081 to Harel et al., which are incorporated herein by reference, describe a method for glucose level control, comprising providing at least one electrode adapted to apply an electric field to a pancreas, and applying an electric field to the pancreas using the electrode such that blood glucose levels are significantly reduced and blood insulin levels are not significantly increased.
PCT Publication WO 03/045493 to Harel et al., which is incorporated herein by reference, describes apparatus for sensing electrical activity of the pancreas. The apparatus includes a set of one or more electrodes, adapted to be coupled to the pancreas, and to generate activity signals indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas.
US Patent Application Publication 2004/0249421 to Harel et al., which is incorporated herein by reference, describes a method for glucose level control, comprising applying an electric field to the pancreas using at least one electrode such that blood glucose levels are significantly reduced, and blood insulin levels are not significantly increased compared to a regular insulin response in a same person. Also described are methods for implanting the electrodes in the pancreas, including: (a) advancing an endoscope to a bile duct, for example via the stomach, and advancing the endoscope through the bile ducts along the pancreas; and (b) advancing an endoscope to the duodenum or other portion of the intestine adjacent to the pancreas, and extending electrodes from the intestine into the pancreas.
U.S. Pat. No. 6,853,862 to Marchal et al., which is incorporated herein by reference, describes a gastroelectric stimulator comprising a neurostimulator for producing a stimulation signal, at least one electrical lead, and at least two electrical contacts. The stimulation signal is adapted to influence pancreatic secretions.
U.S. Pat. No. 5,919,216 to Houben et al., which is incorporated herein by reference, describes a system for automatically responding to insulin demand without any need for external monitoring or injecting of insulin into the diabetic patient. The system provides for sensing glucose levels internally, and responding by stimulating either the pancreas or a transplant of pancreatic islets in order to enhance insulin production. The enhancing stimulation is delivered at a rate greater than the burst rate, or is otherwise controlled so that the depolarization burst constitutes a greater portion of each islet electrical cycle, thereby resulting in increased insulin production. In another embodiment, the system responds to a food intake signal, either externally or internally generated, by going through a time response algorithm to provide a stimulation-enhanced insulin response which simulates the natural response.
U.S. Pat. No. 6,135,978 to Houben et al., which is incorporated herein by reference, describes an implantable system and method for monitoring pancreatic beta-cell electrical activity in a patient in order to obtain a measure of a patient's insulin demand and blood glucose level. A stimulus generator is controlled to deliver stimulus pulses so as to synchronize pancreatic beta-cell depolarization, thereby producing an enhanced electrical signal which is sensed and processed. The insulin demand signal is used either to control delivery of insulin from an implanted insulin pump, or to control ongoing pancreatic stimulation of a form to enhance insulin production.
U.S. Pat. No. 6,832,114 to Whitehurst et al., which is incorporated herein by reference, describes techniques for introducing one or more stimulating drugs and/or applying electrical stimulation to the pancreas and/or nerve fibers innervating the pancreas to treat or prevent diabetes and/or to modulate pancreatic endocrine secretions.
Intragastric balloons for reducing the volume of the stomach to treat obesity have been described, including in the following patents and patent application publications, all of which are incorporated herein by reference: U.S. Pat. Nos. 4,416,267 and 4,899,747 to Garren et al., U.S. Pat. No. 4,694,827 to Weiner et al., U.S. Pat. No. 4,723,547 to Kullas et al., U.S. Pat. No. 4,739,758 to Lai et al., U.S. Pat. No. 5,234,454 to Bangs, U.S. Pat. No. 6,454,785 to De Hoyos Garza, U.S. Pat. No. 6,733,512 to McGhan, US Patent Application Publication 2003/0158569 to Wazne, US Patent Application Publication 2005/0004430 to Lee et al., PCT Publication WO 03/055420 to Lointier et al., PCT Publication WO 04/089262 to Paganon, and PCT Publication WO 87/00034 to Taylor.
U.S. Pat. No. 6,579,301 to Bales et al., which is incorporated herein by reference, describes an intragastric balloon device that includes a flexible bladder, a relatively rigid reservoir coupled to the bladder and adapted to hold a bladder inflation fluid, and an inflation/deflation system adapted to move or permit movement of the fluid from the reservoir and into the bladder. The intragastric balloon device is sized such that it may be positioned, in its entirety, into the stomach cavity. Various systems may be used to move or permit movement of the fluid. A control system is provided to automatically activate the inflation/deflation system. The automatic activation may be activated by a combination of one or more of a timer, the temperature of the stomach, the pressure in the stomach, the mechanical stress in the stomach, or another sensed condition.
U.S. Pat. No. 5,868,141 to Ellias, which is incorporated herein by reference, describes an endoscopic stomach insert for treating obesity in humans by reducing the desire for eating, comprising a base that is sized for passing through a human mouth and esophagus; a plurality of flexible blades coupled at one end thereof to the base and circumferentially arranged about the base central axis, where the blades are biased to extend substantially radially outward and downward from the base; and a retainer for releasably coupling the distal portions of the blades within close proximity to each other about the central axis of the base. The insert is thus adapted to be passed through the mouth and esophagus and into the stomach, and upon releasing the retainer within the stomach, the blades are biased to flare outwardly into the form of a dome-shaped cage, applying pressure to the stomach, and thus causing a sensation of fullness within the stomach and reducing the desire for eating.
PCT Publication WO 05/051486 to Mintchev, which is incorporated herein by reference, describes a method and apparatus for gastrointestinal motility control. An aspect of the invention is described as a method and apparatus for overriding the spontaneously existing gastrointestinal (GI) motility and producing artificial peristalsis completely asynchronously with the spontaneously existing mechanical phenomena in the GI tract, in a given GI organ, or in a portion thereof, using trains of external voltages with a wide range of frequencies (5-50,000 Hz), wide range of duty cycles (10-100%) and wide range of amplitudes (3-30 V peak-to-peak). Also described is a method and apparatus for producing preliminary externally controlled contractions in the sphincter region or regions of the GI organ or in a portion of it (for example, the pylorus in the stomach). The adjacent acetylcholine (ACh) patches in the vicinity of the sphincter region are exhausted due to the prolonged invoked contractions, so that the sphincter inevitably relaxes as a result. Additionally, apparatus invokes externally-controlled GI peristalsis after this sphincter relaxation is achieved, so that content is propelled through the sphincter. Also described is an implantable microsystem device to treat morbid obesity, which can make use of the same device.
PCT Publication WO 02/092165 to King, which is incorporated herein by reference, describes an embodiment in apparatus is adapted for blocking activation of electrically excitable tissue, and more particularly for producing a desired effect by activating tissue at a first predetermined site and for reducing a corresponding undesired side effect by blocking activation of tissue or conduction of action potentials at a second predetermined site. The desired effect may be peristalsis of the patient's intestine; the undesired effect may be closure of the patient's ileocecal valve to the patient's colon. The first site may be the patient's intestinal wall smooth muscle, hypogastric plexus, or nerves to the patient's hypogastric plexus; and the second site may be the patient's ileocecal valve, mesenteric ganglia, dorsal root, spinal dorsal columns, or splanchnic nerves.
The following references, which are incorporated herein by reference, may also be of interest:    EP 1 392 393 B1 to King    U.S. Pat. No. 6,895,279 to Loeb et al.    U.S. Pat. No. 5,423,872 to Cigaina    US Patent Application Publication 2002/0072779 to Loeb    U.S. Pat. No. 6,571,127 to Ben-Haim et al.    U.S. Pat. No. 6,826,428 to Chen et al.    US Patent Application Publication 2003/0055467 to Ben-Haim et al.    US Patent Application Publication 2005/0085923 to Levine et al.    U.S. Pat. No. 6,684,105 to Cohen et al.    PCT Patent Publication WO 03/018118 to Cohen et al. and U.S. patent application Ser. No. 10/488,334 (granted as U.S. Pat. No. 7,734,355 to Cohen) in the national phase thereof    U.S. Pat. No. 6,993,391 to Flesler et al.    U.S. Pat. No. 7,006,871 to Darvish et al.    PCT Publication WO 06/018851 to Kliger et al.    PCT Publication WO 04/112563 to Ben-Haim et al.    PCT Publication WO 05/087310 to Harel et al.    US Patent Application Publication 2006/0085045 to Harel et al.
An article by Kalloo et al., entitled, “Flexible transgastric peritoneoscopy: A novel approach to diagnostic and therapeutic interventions in the peritoneal cavity,” Gastrointest Endosc. 2004 July; 60(1): 114-7, which is incorporated herein by reference, describes testing of an endoscopic peroral transgastric approach to the peritoneal cavity in a porcine model in acute and long-term survival experiments. Transgastric peritoneoscopy was evaluated in 50-kg pigs. After upper endoscopy, the peritoneal cavity was accessed by needle-knife puncture of the gastric wall, followed by extension of the incision either with a pull-type sphincterotome or by balloon dilation. The peritoneal cavity was examined, and a liver biopsy specimen was obtained. The gastric wall incision was closed with clips. Twelve acute and 5 survival experiments were performed. Both techniques of gastric wall incision were without complication. The acute experiments demonstrated the technical feasibility of the approach. In the survival experiments, all pigs recovered and gained weight. The article concluded that the peroral transgastric approach to the peritoneal cavity is technically feasible and has the potential to be an alternative to laparoscopy and laparotomy.
An article by Sun et al., entitled, “Intestinal electric stimulation decreases fat absorption in rats: Therapeutic potential for obesity,” Obes Res. 2004 August; 12(8):1235-42, which is incorporated herein by reference, describes a study investigating whether intestinal electric stimulation (IES) would reduce fat absorption and, thus, would be a potential therapy for obesity. Forty rats implanted with serosal electrodes and two jejunal cannulas were divided into 4 groups of 10 each: control (no stimulation), IES with long pulses, IES with trains of short pulses, and IES with trains of short pulses plus treatment with lidocaine. Jejunal transit and fat absorption of a 20-cm jejunal segment (between two cannulas) were investigated during a 45-minute period with or without IES. It was found that both methods of IES accelerated intestinal transit measured by recovery of phenol red and increased the percentage of triglycerides recovered from the distal cannula in comparison with the control group. IES with trains of short pulses was more effective than IES with long pulses in accelerating jejunal transit and reducing fat absorption. Neither of the two IES methods altered the output of fatty acids from the distal cannula. The effects of IES with trains of short pulses on the transit and fat absorption were partially abolished with the treatment of lidocaine. It was concluded that IES accelerates intestinal transit and reduces fat absorption, suggesting a therapeutic potential for obesity. IES with trains of short pulses was found to be more effective than IES with long pulses, and its effects are partially mediated by enteric nerves, jejunum.
An article by Giralt M et al., Neurogastroenterol Motil. April, 2000, 12(2):173-80, entitled, “Inhibition by CCK of ascending contraction elicited by mucosal stimulation in the duodenum of the rat,” which is incorporated herein by reference, states that CCK released by intraluminal stimuli modifies duodenal activity, contributing to a decrease in gastric emptying. The article notes that the neural mechanisms by which CCK controls motility are not well known. The aim of this study was to investigate the interaction between CCK and the enteric nervous system through the study of the effects of CCK-8 on ascending excitation. Anaesthetized Sprague-Dawley rats were prepared with a strain-gauge sutured to the duodenum wall. An electrode holder was placed in the duodenum lumen to elicit ascending contraction. Electrical field stimulation of the duodenal mucosa (4 Hz, 0.6 ms, 30 V) induced an ascending excitation which was blocked by hexamethonium and atropine, but enlarged by L-NNA. CCK-8 blocked ascending excitation and an inhibition of the induced phasic activity was observed instead. In conclusion, CCK-8 blocked ascending contraction elicited by electrical field stimulation of duodenal mucosa by means of simultaneous activation of CCK-A and CCK-B receptors.
An article by Mukhopadhyay A K et al., Am J. Physiol. January, 1977, 232(1):E44-7, entitled, “Effect of cholecystokinin on myoelectric activity of small bowel of the dog,” which is incorporated herein by reference, describes an experiment in which the effect of cholecystokinin on the myoelectric activity of the small intestine was determined in conscious dogs. Six animals were implanted with electrodes along the small intestine, and a cannula was placed in the stomach. A second cannula was inserted into the duodenum in three animals, and a pancreatic fistula was prepared in three animals. Recordings were made in the fasted state, during the intravenous infusion of either saline or cholecystokinin-octapeptide (CCK-OP), during the intraduodenal infusion of either saline or L-tryptophan, and during the fed state. CCK-OP disrupted the fasted pattern of myoelectric activity, caused a dose-dependent increase in spike potentials, and caused a dose-dependent increase in pancreatic protein secretion. Stimulation of myoelectric activity occurred at doses that produced submaximal protein secretion; however, the stimulation was not identical to that seen with feeding. Intraduodenal infusion of L-tryptophan increased pancreatic protein secretion, interrupted the fasted pattern of motility, and induced a pattern similar to that seen with feeding. The article concluded that CCK alters small intestinal motility and may play a role in the changes in small-bowel motility caused by the ingestion of food.
The following articles, which are incorporated herein by reference, may be of interest:    Bergman, R N et al., “The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes,” Eur J Clin Invest 32(Suppl. 3):35-45 (2002)    Chiasson, J L et al., “Prevention of type 2 diabetes: Insulin resistance and β-cell function,” Diabetes 53(Suppl. 3):S34-S38 (2004)    Kahn S E, “The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes,” Diabetologia 46: 3-19 (2003)    Toyama M T et al., “Effect of ethanol on pancreatic interstitial pH and blood flow in cats with chronic pancreatitis,” Annals of Surgery 225(2):223-228 (1997)    Liu S et al., “Therapeutic potential of duodenal electrical stimulation for obesity: Acute effects on gastric emptying and water intake,” Am J Gastroenterol, 100(4):792-6 (2005).